Previously we determined that HIV gp120 binds to the integrin alpha4-beta7, the gut-homing receptor. On CD4+ T cells, gp120 engagement of alpha4-beta7 results in rapid activation of LFA-1, which is known to increase HIV replication because LFA-1 is the main integrin involved in establishing virological synapses. We then demonstrated that alpha4-beta7high CD4+ T cells are more susceptible to productive infection than alpha4-beta7low-negative CD4+ T cells, in part because the alpha4-beta7high cellular subset is enriched with metabolically active CD4+ T cells. Alpha4-beta7high CD4+ T cells are CCR5high and CXCR4low. On these cells, we found that alpha4-beta7 appears in a complex with CD4. This is the first demonstration that these two receptors appear together in a complex on the surface of a CD4+ T cell. Of note, alpha4-beta7high CD4+ T cells are found in the genital mucosa. Considering the inefficiency of HIV transmission, we explored the role of alpha4-beta7 in HIV pathogenesis and in the basic underlying mechanisms of HIV transmission and HIV-mediated immune dysfunction. To this end, we analyzed HIV gp120s from early transmitted viruses (founder viruses). We observed that founder viruses have an increased affinity for alpha4-beta7 and that this binding is affected by glycosylation, consistent with the signature of transmission-linked viral isolates. The delineation of the role of alpha4-beta7 in HIV pathogenesis provides critical new information for understanding the basic mechanisms underlying HIV transmission and HIV-mediated immune dysfunction.